Addictiontopsychostimulantssuchascocainerepresentsamajorpublichealthissueexactingtremendous financialandsocialcosts.Despitethis,psychostimulantusedisorderremainsarecalcitrantconditionwithno currentlyFDA-approvedmedicationsforitstreatment.Inmanyfieldsofpsychiatricresearch,thelinkbetween thebrainandtheimmunesystemhasbeenheavilystudiedasawaytodeterminepathophysiologyandtofind newmethodsoftreatment.Whileitisknownthatcocainecanalterthefunctionofboththeinnateandadaptive immunesystems,thelinkbetweentheseimmunechangesandmaladaptivedrugtakingandseekingbehaviors remainsminimallyexplored.Inaseriesofinitialexperiments,weexaminedhowexperimenterorself- administeredcocainealteredtheserumprofileof32cytokines.Ofthese,wefoundthatgranulocyte-colony stimulatingfactor(G-CSF)wasincreasedbycocaine,andtheserumlevelsshowedlinearcorrelationwith behavioralresponsetococaine.Behaviorally,injectionsofG-CSFalterthedose-responsecurveforcocaine placepreference,andfacilitateextinctionandreducereinstatementofcocaineseeking.Takentogether,these preliminarystudiesdemonstratethatG-CSFisapotentmodulatorofcocaine-inducedbehavioralplasticity,and maybeapotentialtherapeutictargetforprolongingabstinenceincocaineusedisorder.Underthementorship ofDrs.EricNestlerandYasminHurdIwillseektofurtherclarifytheroleofG-CSFinaddictionwhilegaining additionaltrainingtoallowmetotransitiontoindependence.InAim1ofthisproposalIwillinterrogatethe effectsofG-CSFinthenucleusaccumbens(NAc)inacell-typespecificmannerbyusingviralvectorstoknock downtheG-CSFreceptorinpopulationsofD1andD2positivemediumspinyneuronspriortococaineself- administration,extinctionandreinstatement.Theseexperimentswillprovideinsightintothemicrocircuitry underlyingthebehavioraleffectofG-CSF,andwillprovidemecrucialtraininginself-administrationand targetedmanipulationofgeneexpression.InAim2,IwillseektoidentifyG-CSFresponsivegenesinNActhat accountforitsbehavioraleffect.IwillperformmRNAsequencingoftheNAcfromanimalsself-administering cocaine,followedbydifferentialexpressionandpathwayanalysis.Thebehavioraleffectofhighlyregulated genesandpathwayswillbeinterrogatedbyviralgenemanipulationpriortococaineself-administration, extinctionandreinstatement.Theseexperimentswillprovidemewithcrucialmentoringincreation,analysis andutilizationoflargesequencingdatasets,whilealsoprovidingdetailedinformationastohowG-CSFaffects cocaine-relatedbehavioralplasticity.Insummary,theresearchproposedinthisawardwillelucidatetheneural andmolecularmechanismsofatranslationally-relevanttreatmenttarget,whileprovidingmewithsufficient mentorshiptotransitionintoanindependentinvestigator.